All movements are executed as a result of graded activation of different muscles. Muscle activity is controlled by the activation of motoneurons in the brainstem and spinal cord. Each motoneuron drives the muscle fibers it innervates in a one-to-one fashion, thus forming a motor unit. Because muscle fiber action potentials are relatively easy to measure, motoneurons are the only CNS cells whose firing patterns can be readily quantified in human subjects. The cellular mechanisms that drive these firing patterns, however, can only be measured via intracellular studies in animal preparations. The goal of this proposal is to develop a sophisticated computer simulation platform to quantitatively link cellular data from animal preparations to firing pattern data in human subjects. Highly realistic models of human motoneurons will be implemented on field programmable gate arrays (FPGAs). We will employ these models to quantify our present state of knowledge about cellular mechanisms of human motoneuron firing patterns. The simulations will then be used to generate predictions for further experiments both in humans and animals, with the goal of identifying mechanisms underlying the severe deficits in firing patterns that occur in hemiparetic stroke patients. The overall hypothesis of this proposal is that these deficits in firing patterns are primarily due not to alterations in the synaptic input to motoneurons but instead to changes in their intrinsic electrical properties. Normally, motoneuron intrinsic properties are controlled by descending neuromodulatory inputs from the brainstem that release the monoamines serotonin (5HT) and norepinephrine (NE). Thus, changes in intrinsic properties may arise from changes in the input from the brainstem to the spinal cord. The proposal has three specific aims: 1) To develop highly realistic models of human motoneurons using a high-speed (FPGA) simulation platform in conjunction with automatic parameter search algorithms; 2) To use these models to identify potential cellular mechanisms underlying changes in motoneuron firing patterns in hemiparetic stroke; and 3) To carry out new experiments in humans and animal models to test predictions developed in the Aim 2 model analyses. The results of these studies have the potential for substantial clinical impact. Drugs that mimic the effects of two important motoneuron neuromodulators, the monoamines 5HT and NE, have especially strong actions on these cells' properties. Thus, the proposed work will not only provide a new level of understanding of cellular properties of human motoneurons, but also guide development of therapeutic strategies to restore normal motoneuron discharge patterns in stroke patients. PUBLIC HEALTH RELEVANCE: Cerebral strokes commonly result in a number of movement deficits on the side of the body opposite the stroke (hemiparesis). The proposed research combines computer simulations with experimental recordings in hemiparetic stroke subjects and in animal models to determine the mechanisms underlying movement deficits following stroke. The proposed work will not only provide a new level of understanding of the cellular properties of the cells that drive muscle activity, but also guide development of therapeutic strategies to restore normal muscle activation in stroke patients.